Mechanisms of HOX Protein Mediated Transformation

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DESCRIPTION (provided by applicant): Overexpression of the homeobox gene HOXA9 is emerging as an important mechanism of deregulated growth in both myelodysplasia and acute lymphoid and myeloid leukemias. HOXA9 is expressed at high levels in acute leukemias with MLL rearrangements, in myelodysplastic disorders and in high risk AMI. By itself, HOXA9 is a weak oncogene. However, in tumors, HOXA9 is almost always coexpressed with MEIS1, a HOX cofactor. Furthermore, HOXA9 and MEIS1 strongly cooperate to produce leukemia in animal models. Understanding the molecular basis for this cooperativity is pivotal for developing targeted therapy. Two general mechanisms of cooperativity are possible. One involves direct physical interaction between HOXA9 and MEIS1. This could result in altered HOXA9 localization or stability or change the affinity or specificity of HOXA9 in binding to transcriptional targets. Alternatively, HOXA9 and MEIS1 may regulate distinct pathways that cooperate in leukemogenesis. Progress toward this goal has been hampered by lack of knowledge of the proteins associated with HOXA9 and lack of insight into downstream targets of HOXA9 and MEIS1. In this proposal, two strategies would be pursued for identifying proteins associated with HOXA9 in cells transformed by HOXA9. We will determine if more than one HOXA9 complex exists in leukemia cells and what the role of the abundantly expressed HOXA9T isoform is on transformation. We will determine if MEIS1 overexpression affects the localization and composition of HOXA9 complexes and if reducing HOXA9 or MEIS1 expression blocks transformation. Cell lines with conditional forms of HOXA9 and MEIS1 or knock down will be used to identify direct and indirect targets of HOXA9. Using bioinformatics tools, we will identify and characterize regulatory elements responsive to HOXA9 in hematopoietic cells. Overall, this work will provide mechanistic insights into HOXA9 mediated transformation and is likely to uncover promising new therapeutic targets in myelodysplasia and leukemia.